Both in vivo and in vitro, DFMO is an enzyme activated irreversible inhibitor of ornithine decarboxylase (ODC) which is responsible for the conversion of L-ornithine to putrescine, which in turn is converted to longer chain polyamines such as spermidine and spermine. These longer chain polyamines are required for cellular proliferation. Therefore, by inhibiting ODC, DFMO suppresses polyamine formation and consequently cellular proliferation. Aberrant and accelerated cellular proliferation occurs in carcinogenic tissues. Since DFMO is able to suppress polyamine formation, it is able to suppress cellular proliferation and ultimately to ameliorate or prevent cancer. A number of animal studies and/or human clinical trials relate to use of racemic DFMO and specific neoplastic disorders. In addition, a clinical study to determine the pharmacokinetics of racemic DFMO in healthy men has been reported. (Haegele, 1981). Racemic DFMO was reported to have a short elimination half-life, i.e., t.sub.1/2 is about 3.5 hours, as it undergoes rapid renal elimination. Peak plasma concentrations occur within about 6 hours after oral administration of racemic DFMO containing solutions. Mean total body clearance is about 1.20 mL/min/LcKg, where mean renal clearance is about 0.99 mL/min/LcKg accounting for 83% of drug elimination. The mean apparent volume distribution is about 0.337 L/LcKg, corresponding to 24 L for a 70 LcKg man. The amount of unchanged drug in 24-hour urine samples is about 44% after oral administration and about 80% after L.c. administration.
At a dose of about 3 g/m.sup.2 V, a steady state level of DFMO, 386-622, .mu.M may be achieved. A DFMO dose of 2.25 g/m.sup.2 every six hours has been recommended for Phase II studies in patients previously treated with cytotoxic drugs (Abeloff et al., 1984).
The maximally tolerated dose (MTD) of oral DFMO has also been examined (Abeloff et al., 1984). The MTD of a 4-day DFMO course given orally, by CI, or by pulse IV infusions (Griffin et al., 1987) to patients with advanced solid tumors or lymphomas has also been studied. Some patients receiving twenty-four courses of oral DFMO on a 28-day schedule developed thrombocytopenia (the DLT). Gastrointestinal side effects have also been observed in treated patients (Abeloff et al., 1984). Audiometric abnormalities is a further side effect associated with DFMO treatment (Griffin et al., 1987). No therapeutic responses were noted in these patient populations.
A study by Griffin et al. (1987) compared routes (PO, CI and IV) and schedules (bolus and continuous infusions) of DFMO administration. Nausea and vomiting were the most frequent and severe toxicities noted, but this occurred mainly in patients receiving oral DFMO. Diarrhea was also observed in patients receiving oral DFMO. Mild leukopenia was further observed with all routes of administration. Mild thrombocytopenia also occurred in some patients. No therapeutic responses were reported with any route of drug administration.
The known minimum effective dose (MED) for racemic DFMO in significantly reducing polyamine pools in vivo is about 0.43 g/day. The maximum tolerated dose of these preparations reported is about 12 g/m.sup.2 /day (oral administration). The reported minimum toxic dose for these racemic preparations of DFMO, in terms of ototoxicity, is about 150 g/m.sup.2 cumulative dose based upon 0.25-6.0 g/m.sup.2 /day chronic oral administration. GI toxicity occurs predominantly during P.O. rather than I.V. administration of racemic DFMO preparations. (-)-DFMO has been reported by some to be the enantiomer primarily responsible for ODC inhibition (Danzin, 1987). However, the side effects associated with DFMO have been traced to a particular enantiomeric form.
Tricalcium phosphate (TCP) and aluminum calcium phosphate (AlCAP) capsule formulations have been tested as implants in rats and proposed for the treatment of trypanosomiasis. (Benghuzzi et al., 1988) A layered tablet formulation comprising racemic DFMO and a slow release layer compressed to a rapid release layer has been tested for controlling fertility and gestation in rat and mouse models. (Bey et al., U.S. Pat. No. 4,309,442). Conventional release hard gelatin capsule and tablet formulations comprising racemic DFMO are also known and have been tested in rat, dog and/or mouse models for controlling gestation, treating non-malignant proliferative skin diseases and/or cancer chemoprevention. (Bey et al., U.S. Pat. No. 4,496,588).
A need continues to exist in the medical arts for formulations capable of maintaining high plasma levels of DFMO during therapy in spite of its rapid clearance rate, without the toxic andlor non-pleasant side effects associated with available DFMO therapies.